PROJECT SUMMARY The consequences of Alzheimer?s disease (AD) pathology on brain function are not fully understood, particularly in earlier stages of disease, prior to widespread synaptic and neuronal loss, when cognitive function is still largely maintained. The goal of this R21 exploratory project is to investigate the effect of AD pathology in well-characterized clinically normal participants on brain metabolism (FDG-PET), and on functional connectivity (fcMRI), utilizing participants from the Harvard Aging Brain Study (HABS). We are looking for specific evidence of disrupted neuronal function resulting in a phase of hyperactivity associated with both elevated FDG signal and increased functional coherence, consistent with predictions from the excitotoxic hypothesis of induced neuronal hyperactivity by AD molecular pathology. We also focus on associations between FDG and fcMRI to better understand the relationships between these prominent functional imaging modalities. There are three components to this project that will leverage and augment current research efforts. 1) Simultaneous FDG fMRI acquisition, which will be critical for tying together measures of functional connectivity (fMRI) and metabolism (FDG). 2) Long fcMRI acquisitions, which are essential for investigating dynamic functional connectivity. 3) Constrained behavioral state, which will introduce a measure of experimental control for understanding changes in brain connectivity and in brain dynamics as compared to unconstrained resting state. These unique data, coupled with prior assessment with amyloid-PET, tau-PET, and extensive clinical and neuropsychological assessment will allow us to more carefully query links between metabolic activity, functional connectivity, and connectivity dynamics with respect to AD molecular pathology. Our goal is to better understand whether hyperconnectivity is associated with elevated metabolic activity in individuals with biomarker evidence of preclinical AD. An important extension of that general goal is the investigation of functional dynamics within constrained and unconstrained behavioral states as well as contrastive differences in connectivity and dynamics between constrained and unconstrained behavioral states. Our central thesis is that early stage AD molecular pathology will be associated with elevated FDG metabolism, which will be associated with a loss of dynamic flexibility, which will manifest as increased connectivity strength; and we hypothesize that these effects will be accentuated when participants are in a constrained cognitive state. This project will generate a highly informative dataset that will guide future research directions and inform the implementation and interpretation of functional imaging in clinical trials. This exploratory study will help point the way forward for constrained state fcMRI, inform the degree to which FDG relates to or helps contextualize connectivity effects, and inform predictions regarding the readout of functional imaging response to interventional treatment in clinical trials across different stages of AD progression.